There are a number of reasons why a particulate active substance (such as a drug) might need a protective barrier at the particle surfaces. The active substance may be physically or chemically unstable, or incompatible with another substance with which it needs to be formulated. It may need protection against, for example, moisture, light, oxygen or other chemicals. A surface coating may alternatively be needed to delay release of the active substance for a desired time period or until it reaches an appropriate site, or to target its delivery to such a site. Drugs intended for oral administration may need coatings to mask their flavour and render them more palatable to patients.
To protect an active substance in this way, a protective additive needs to be coated onto the external surfaces of the active particles. Several methods are known for applying such coatings. Traditional pan or fluidised bed techniques apply a fluid coating directly to solid active particles. Alternatively, a thin film layer of a coating material may be deposited onto particle surfaces by adding the particles to a solution of the coating material and then removing the solvent, for instance by evaporation, spray drying or freeze drying. Plasticisers, such as polyethylene glycol (PEG), may be added to the solution to enhance coating flexibility and surface adhesion. This technique is widely used in the pharmaceutical industry to coat solid drug dosage forms such as tablets, granules and powders.
With changing trends in drug delivery, there is a growing need for direct coating of drug particles, especially fine particles. Traditional coating methods, as described above, involve several stages such as crystallising, harvesting, drying, milling and sieving of the drug to obtain particles of the desired size range, and a subsequent, separate, coating step. This increases the risks of product loss and contamination.
The coating of microfine particles, for instance in the range 0.5–100 μm, has often proved particularly problematic due to the large surface area of the particles and the non-uniform, often incomplete, coatings achieved using traditional pan or fluidised bed coating techniques. Problems can be particularly acute if the particles are irregular in shape. If the material to be coated is water soluble, organic solvents are needed for the coating solution, which can lead to toxicity, flammability and/or environmental problems. The coatings achieved can often cause problems such as increased particle aggregation and increased residual solvent levels, which in turn can have detrimental effects on downstream processing.
In the particular case of taste masking coatings, the need for a continuous and uniform coating layer is particularly great, since any discontinuity in the coating, allowing release of even the smallest amount of a poor tasting active substance, is readily detectable. Thus, the above described problems with prior art coating techniques assume even greater significance in the case of taste masking.
Recent developments in the formation of particulate active substances include processes using supercritical or near-critical fluids as anti-solvents to precipitate the active substance from solution or suspension. One such technique is known as SEDS™ (“Solution Enhanced Dispersion by Supercritical fluids”), which is described in WO-95/01221 and, in various modified forms, in WO-96/00610, WO-98/36825, WO-99/44733, WO-99/59710, WO-01/03821 and WO-01/15664, which are hereby incorporated in their entirety by reference. The literature on SEDS™ refers to the possibility of coating fine particles, starting with a suspension of the particles in a solution of the coating material (see in particular WO-96/00610, page 20 line 28-page 21 line 2, also WO-95/01221 Example 5).
Distinct from the coating of particulate actives, it is also known to mix active substances such as drugs with excipients (typically polymers) which serve as carriers, fillers and/or solubility modifiers. For this purpose the active substance and excipient are ideally coformulated to yield an intimate and homogeneous mixture of the two. Known techniques include co-precipitation of both the active and the excipient from a solvent system containing both. The SEDS™ process may also be used to coformulate in this way, as described for instance in WO-95/01221 (Examples 10 and 16), WO-01/03821 (Examples 1–4) and WO-01/15664.
The products of coformulation processes are generally intimate mixtures of the species precipitated, for instance a solid dispersion of a drug within a polymer matrix. This is particularly the case for the products of a very rapid particle formation process such as SEDS™ (see the above literature). Indeed, because prior art coformulations have for the most part been motivated by the need to modify the dissolution rate of an active substance, they have concentrated (as in WO-01/15664) on obtaining truly homogeneous mixtures of the active and excipient(s), with the active preferably in its more soluble amorphous, as opposed to crystalline, state.
Whilst such a high degree of mixing is desirable for many products, it is clearly not appropriate where the additive is a surface protector or taste masking agent, since it leaves at least some of the active substance exposed at the particle surfaces, whilst “tying up” a significant proportion of the additive within the particle core. In the case of an unpleasant-tasting drug, even very tiny amounts at the particle surfaces can be sufficient to stimulate the taste buds, despite the additional presence of a taste masking agent.
Where such prior art formulations failed to achieve a completely homogeneous dispersion of the active in the excipient, for instance at higher active loadings, SEM analysis suggested that they contained domains of purely crystalline, excipient-free active substance. These domains would be expected to be surrounded by a second phase containing a homogeneous mixture of the remaining active and the excipient. This too would be highly undesirable for taste-masked or otherwise surface-protected systems; at least some of the active would still be present at the particle surfaces. For this reason, active/excipient coformulation has tended to be used for systems containing lower active loadings, in order to achieve intimate homogeneous mixtures of the active (preferably in its amorphous phase) and the excipient. Alternative techniques, using physically distinct active and excipient phases, have been used to achieve coating of actives, especially at relatively high active:excipient ratios.
Thus coformulation, in particular via SEDS™ as in WO-01/15664, has not previously been used to coat active substances with protective agents such as taste maskers.